Bahjat FR et al. – A novel spleen tyrosine kinase (Syk)-selective inhibitor prevents the development of renal disease and treats established murine lupus nephritis, suggesting that Syk inhibitors may be of therapeutic benefit in human lupus and related disorders. Methods
Aim was to assess if R788, an orally bioavailable small molecule inhibitor of Syk-dependent signaling, could modulate disease in lupus-prone mice via inhibition of Fc receptor (FcR) and B cell receptor signaling
R788 was administered to mice before and after disease onset
Proteinuria, blood urea nitrogen levels, and autoantibody titers were examined periodically
Overall survival and renal pathologic features were assessed following long-term treatment (24-34 weeks)
The distribution and immunophenotype of various splenic T cell and B cell subpopulations were evaluated at the time of study termination
Arthus responses in mice pretreated with R788 or Fc-blocking antibody were also examined
Results
R788 delayed the onset of proteinuria and azotemia, reduced renal pathology and kidney infiltrates, and significantly prolonged survival of lupus-prone mice
Autoantibody titers were minimally affected throughout the study
Dose-dependent reductions in the numbers of CD4+ activated T cells expressing high levels of CD44 or CD69 were apparent in spleens from R788-treated mice
Minimal effects on the numbers of naive T cells expressing CD62 ligand and total CD8+ T cells per spleen were observed following long-term drug treatment
R788 pretreatment resulted in reduced Arthus responses in mice, similar to results obtained in mice pretreated with FcR-blocking antibody
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